Doxorubicin cytotoxicity

Fig. 20.10. Enhancement of doxorubicin cytotoxicity in LoVo-resistant cells by verapamil and analogues. (Adapted from Ref. [77]). The results are expressed as fold increase in cytotoxicity represented by the ratio of doxorubicin IC50 in the absence and presence of verapamil and analogues (solid bars). The verapamil concentrations used were the minimal cytotoxic concentrations (IC20)-The compounds used were verapamil (1) ...

Gao, J.-P. et al. (1993) The role of reduced nicotinamide adenine dinucleotide phosphate in glucose- and temperature-dependent doxorubicin cytotoxicity, Cancer Chemother. Pharmacol. 33, 191-196. 

Veldman, R.J., Zerp, S., van Blitterswijk, W.J., and Verheij, M. N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx. Br J Cancer, 90, 2004, 917-925. 

Doxorubicin treatment induced disruption of inner mitochondrial membrane potential Atjin, that precedes the nuclear signs of apoptosis (Decaudin et al. 1997). Both loss of At ini and apoptosis were prevented by Bcl-2 overexpression (Antoku et al. 1997, Decaudin et al. 1997), suggesting an important role for mitochondria in doxorubicin-induced apoptosis. Western blot analysis of Jurkat cell extracts indicated that caspases 2,3,4,6,7,8,9, and 10 were activated by doxorubicin (Gamen et al. 2000). Doxorubicin cytotoxicity was blocked by the protein synthesis inhibitor cycloheximide. 

Evig, C.B., Kelley, E.E., Weydert, C.J., Chu, Y., Buettner, G.R., and Bums, C.P. (2004). Endogenous production and exogenous exposure to nitric oxide augment doxorubicin cytotoxicity for breast cancer cells but not cardiac myoblasts. Nitric Oxide 10,119-129. 

Figure 3. Dependence of doxorubicin cytotoxicity against drug resistant MCF-7ADR cells on concentration of Pluronic L61 in the medium. The vertical airow shows CMC.

Cytotoxic drugs that have been used alone and in combination as adjuvant therapy in breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil,... 

The calcein-AM assay [82-84] and cytotoxicity assays (e.g., performed with doxorubicin) [77, 78] are both basically competition assays. The accumulation of a primary substrate (e.g., calcein-AM or doxorubicin) in the cytosol of living cells is measured after addition of a second substrate (also called modifier or reverser) that reduces the efflux of the primary substrate. In the case of the calcein-AM assay, the primary substrate, calcein-AM, is hydrolyzed as soon as it reaches the cytosol, and the highly fluorescent hydrolysis product (calcein) can be determined using fluorescence spectroscopy. The more effective the reversal agent, the stronger is the increase in calcein fluorescence. Data can be quantified in terms of inhibitory constants, IQ, of the reversal agent. 

Veronese FM, Schiavon O, Pasut G, Mendichi R, Andersson L, Tsirk A, Ford J, Wu G, Kneller S, Davies J, Duncan R (2005) PEG-doxorubicin conjugates influence of polymer structure on drug release, in vitro cytotoxicity, biodistribution, and antitumor activity. Bioconjug Chem 16 775-784... 

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

Bogdanovic G, Kojic V, Dordevic A, Canadanovic-Brunet J, Vojinovic-Miloradov M, Baltic VV (2004) Modulating activity of fullerol C60(OH)22 on doxorubicin-induced cytotoxicity. Toxicology In Vitro 18 629-637. 

The so-called self-immolative prodrugs are other relevant and intriguing examples as candidates for ADEPT (Fig. 8.17). Here, the primary bioactivation product is not the active agent, but an intermediate that breaks down spontaneously to liberate this active agent. Various cytotoxic drugs that bear an amino group were investigated, i. e., 4-[bis(2-chloroethyl)amino]aniline, actinomycin D, doxorubicin, and mitomycin C [206]. These were trans-... 

Table 23.1 details all of the recent Food and Drug Administration (FDA)-approved agents. In this section we will detail some interesting aspects of the approach to their development. As can be seen in Table 23.1 there are 21 new entities. Of note is that only seven (33%) of the agents including capecitabine, liposomal doxorubicin, temozolomide, and oxaliplatin, ABl-007, liposomal cytarabine, and pemetrexed could be considered conventional cytotoxic... 

Capranico, G., Babudri, N., and Casciarii, G., 1986, Lack of effect of glutathione depletion on cytotoxicity, mutagenicity and DNA damage produced by doxorubicin in cultured cells. Chem.-Biol. Interact. 57 189-201... 

Horowitz AT, Barenholz Y, Gabizon AA. In vitro cytotoxicity of liposome-encapsulated doxorubicin dependence on liposome composition and drug release. Biochim Biophys Acta 1992 1109 203-209. 

Since the discovery of vesicular structures, termed liposomes, by Alec Bangham, a tremendous amount of work on applications of liposomes has emerged. The use of small unilamellar liposomes as carriers of drugs for therapeutic applications has become one of the major fields in liposome research. The majority of these applications are based on the encapsulation of water-soluble molecules within the trapped volume of the liposomes. Long circulating poly(ethylene glycol) (PEG) modified liposomes with cytotoxic drugs doxorubicin, paclitaxel, vincristine, and lurtotecan are examples of clinically applied chemotherapeutic liposome formulations (1,2). 

Ishida T, et al. Targeted delivery and triggered release of liposomal doxorubicin enhances cytotoxicity against human B l5miphoma cells. Biochim Biophys Acta 2001 1515 144. 

Of the non-antibody, non-liposome based drug targeting strategies, most of the (limited) clinical experience has been obtained with polymer-based conjugates of anticancer drugs. The most widely employed drugs for this application are cytotoxic agents such as doxorubicin and... 

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